This application addresses development of a novel non-invasive depth-resolved optical imaging technique, low-coherence enhanced backscattering spectroscopy (EBS), for colorectal cancer (CRC) screening. CRC remains the second leading cause of cancer death in the U.S. Although colonoscopy is remarkably effective in reducing CRC, screening the entire at-risk population (>60 million Americans over age 50) through colonoscopy is impossible for a variety of reasons including expense, patient reluctance and resource availability. Thus, targeting patients at the highest risk is crucial for designing efficacious and cost-effective CRC screening strategies. Many risk-stratification techniques exploit the "field effect" of colon carcinogenesis, the notion that the genetic/epigenetic alterations that lead to a tumor in one area should be detectable throughout the colon mucosa. Thus, detecting early events in the most readily accessible colonic mucosa (i.e. rectum) could lead to accurate long term risk assessment. However, technological limitations have, to date, stymied this approach. Our data demonstrate that depth-resolved EBS has the ability to detect the micro/nanoscale architectural consequences of the molecular changes in the "field effect" with unprecedented accuracy. This work builds upon our development, for the first time to the best of our knowledge, of EBS spectroscopy for highly sensitive sensing of depth-resolved changes in tissue microarchitecture. Our animal and pilot human studies indicate that EBS markers have performance superior to all conventional markers of CRC. Based on our preliminary data, we hypothesize that EBS interrogation of the rectal mucosa should allow accurate prediction of colonic neoplasia and hence need for colonoscopy. In order to develop EBS for CRC screening, we propose to develop an endoscopically compatible EBS probe and discover new EBS markers. These previous and novel EBS markers will be used to formulate prediction rules for both the presence and absence of neoplasia in 500 patients undergoing colonoscopy. This will then be validated in a prospective clinical study. In the future these spectral markers may be assayed with an EBS fiber-optic probe during a routine rectal examination without the need for bowel preparation, thus providing a practical and accurate means of determining the optimal CRC screening regimen, such as the need for colonoscopy.